This invention relates to a method of treating meningeal leukemia and CNS lymphoma, and neoplasms in the brain in man and pharmaceutical preparations suitable for such use.
More effective antileukemic therapy and consequent longer survival has the unfortunate consort of an increase in the number of human patients developing meningeal leukemia. This is a more common occurrence in children than adults; 50 to 85 percent of the children in whom acute lymphoblastic leukemia has been controlled by chemotherapy have developed leukemic meningitis. Since most drugs used in the treatment of acute leukemia do not pass the blood-brain barrier, the central nervous system may serve as a sanctuary for leukemic cells and may act as a nidus for systemic relapse.
It has been previously demonstrated that 2,4-diamino-5-(3', 4'-dichlorophenyl)-6-methylpryrimidine (DDMP) and, 2,4-diamino-5-(3', 4'-dichlorophenyl)-6-ethylpyrimidine (DDEP) have an inhibitory activity against a variety of cancerous conditions. For example, antitumor activities against mouse Sarcoma 180 [Clarke, et al., Cancer Research, 12, 255(1952)] and against mouse leukemia have been reported in Cancer Research, Burchenal et al., Cancer Research, 12 251, (1952). More recently the treatment of meningeal leukemia with pyrimethamine [2,4-diamino-5-(4'chlorophenyl)-6-ethylpyrimidine], has been reported [Geils, et al. Blood, 38, 131 (1971)].
It is also known that pyrimethamine readily crosses the blood-brain barrier and indeed apparently has easy access to all body compartments and cells [Hitchings, Discussion of paper by Bertino, et al., Fed. Proc. 26, 896 (1967)]. This property assumes great significance in the treatment of leukemia as well as other cancerous conditions involving metastasis.
For example, an effective anti-leukemic agent which could not pass the blood-brain barrier would not be effective against meningeal leukemia, a condition in which leukemic cell infiltration of the arachnoid membrane has occurred. Methotrexate is known to be effective against leukemia and is also known to be unable to cross the blood-brain barrier. Thus, in order for methotrexate to be effectively used against meningeal leukemia it must be administered intrathecally [Geils et al., Blood, 38, 131 (1971)].
Murphy and co-workers [J. Clin. Invest., 33, 1388 (1954)] reported clinical studies of the therapeutic activity of DDMP against leukemia in children and adults as well as against several other cancerous conditions. Significant toxic manifestations characteristic of antagonists of the folic acid system were observed.